Sirtuins are evolutionarily conserved epigenetic proteins involved in diverse cellular processes in both prokaryotes and eukaryotes. Among them, Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. SIRT6 regulates glucose homeostasis in the liver. The overexpression of SIRT6 inhibits the phosphorylation of ERK1/2 and thus attenuates the tumor-suppressive effect in hepatocellular carcinoma (HCC) cells. In particular, SIRT6 is an important protumorigenic factor in liver carcinogenesis. SIRT6 knockdown promotes G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly. Consequently, the effect attributes to DNA damage. The average level of SIRT6 expression in HCC cells is lower than that in primary human hepatocytes. Consequently, SIRT6 acts as a tumor suppressor in various cancers.

In this study, Huang Z, et al reported the identification of MDL-800, a selective SIRT6 activator. MDL-800 increases SIRT6 deacetylation activity with an EC50 value of 10.3±0.3 µM. MDL-800 increases the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site. This interaction leads to a global decrease in H3K9ac and H3K56ac levels in human HCC cells. MDL-800 also causes cell-cycle arrest in HCC cells. MDL-800 inhibits the proliferation of HCC cells via SIRT6-driven cell-cycle arrest. Besides, MDL-800 is effective in a tumor xenograft model. MDL-800 inhibits xenograft tumor growth of HCC cells in immunocompromised mice.

Taken together, the activation of SIRT6 deacetylation by MDL-800 represents a potential therapeutic target for the treatment of HCC.

Huang Z, et al. Identification of a cellularly active SIRT6 allosteric activator. Nat Chem Biol. 2018 Dec;14(12):1118-1126.